Enriching the Arsenal of Pharmacological Tools against MICAL2

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure–activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.     

Clear and pigmented water epoxy systems: a study on the hardening kinetics on the basis of the variations of the viscoelastic moduli

The hardening reaction of a two-can water epoxy polyamide system was investigated on the basis of the variation of the viscoelastic moduli G′ and G′′. Unpigmented (clear varnish) and TiO₂ pigmented formulations, at two different TiO₂ concentrations, were taken into account. Time and frequency sweep procedures were carried out using the stress-controlled rheometer Haake RS 150. The behavior of G′ and G′′ vs time was fitted to a four-parameter asymptotic model through the whole course of the hardening process. Frequency sweep data, obtained at increasing times during the whole hardening process, were plotted to the generalized Cole and Cole behavior model and the corresponding mechanical spectra were drawn. An interpretation for some aspects of the cross-linking progress is discussed and possible future developments are briefly outlined. Received: 15 January 2000 Accepted: 13 November 2000     

Functionalization of Biodegradable Polyester for Tissue Engineering Applications

Summary: Chemical modification of polymer surface may potentially be used to create smart materials that can guide cellular adhesion, proliferation and maintenance of specific expression of molecules. The microbial polyester poly (3-hydroxybutyrate) (PHB) has been attracted attention as promising material for applications in tissue engineering. In this work, a wet-chemical method, base ethylenediamine aminolysis, was performed to improve the adhesion of chondrocytes isolated from human articular cartilage to PHB films. The effects of chemical treatment on PHB films was evaluated by following changes in morphology and surface chemical composition using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS), respectively. While the effect on cells morphology was studied by scanning electron microscopy (SEM). The treatment with ethylenediamine did not change significantly the morphology of the structures of PHB films surface. However, the roughness of the aminolyzed films was slightly higher. The introduction of nitrogen-containing groups was confirmed by XPS. In vitro experiments indicated that the surface modification did not have toxic effects in cells, since they could adhere and proliferate on modified PHB films. It was observed that long-time treatment improved ability of PHB films to support cell growth, which could be accounted to physicochemical and topological effects.     

Rapid SPE-HPLC determination of the 16 European priority polycyclic aromatic hydrocarbons in olive oils

Polycyclic aromatic hydrocarbons (PAHs) are a large class of organic compounds. It has been established that the main source of exposure to these compounds for human beings is through food, particularly fats and oils, due to the lipophilic nature of these polycyclic compounds. The aim of this work was to optimise and validate a method involving SPE and HPLC for rapid determination of the 16 European Union (EU) priority PAHs (required by the Recommendation 2005/108/EC) in vegetable oils. Two spectrofluorometric detectors and a UV-Visible detector in series were used to identify and quantify the target compounds. Linearity, recoveries, LOD, and LOQ were found to be in agreement with the performance criteria for benzo[a]pyrene (BaP) analysis as required by the Commission Directive 2005/10/EC, and satisfactory for all the compounds of interest, except for cyclopenta[c,d]pyrene, which presented a very low signal in the UV. Optimised chromatographic conditions for the separation of 25 PAHs, comprising both EPA and EU priority PAHs plus benzo[e]pyrene and benzo[b]chrysene, have been also proposed.     

Synthesis of New Heterocyclic Ring Systems via [1,3,5]Triazino[1,2‐a]benzimidazole Derivatives

Three new heterocyclic ring systems were synthesized from [1,3,5]triazino[l,2‐a]benzimidazole derivatives, which in turn were obtained by condensation of 2‐guanidinobenzimidazole with o‐substituted ben‐zaldehydes.     

Inclusion complex characterization between progesterone and hydroxypropyl-β-cyclodextrin in aqueous solution by NMR study

The aim of this work is the determination of the molecular association of progesterone (P) with hydroxypropyl-β-cyclodextrin (HPβCD) in aqueous solution. The stoichiometry and the binding constants of the inclusion complex were calculated using NMR techniques.     

Theoretical and electrochemical analysis of dissociative electron transfers proceeding through formation of loose radical anion species: reduction of symmetrical and unsymmetrical disulfides

The dissociative reduction of a series of symmetrical (RSSR, R = H, Me, t-Bu, Ph) and unsymmetrical disulfides (RSSR', R = H, R' = Me and R = Ph, R' = Me, t-Bu) was studied theoretically, by MO ab initio calculations and, for five of them, also experimentally, by convolution voltammetry in N,N-dimethylformamide. The reduction is dissociative but proceeds by a stepwise mechanism entailing the formation of the radical anion species. The electrochemical data led to estimated large intrinsic barriers, in agreement with an unusually large structural modification undergone by the disulfide molecules upon electron transfer. The theoretical results refer to MP2/3-21G*//MP2/3-21G*, MP2/3-21*G*//MP2/3-21G*, CBS-4M, and G2(MP2), the latter approach being used only for the molecules of small molecular complexity. A loose radical-anion intermediate was localized and the dissociation pattern for the relevant bonds analyzed. For all compounds, the best fragmentation pathway in solution is cleavage of the S-S bond. In addition, S-S bond elongation is the major structural modification undergone by the disulfide molecule on its way to the radical anion and eventually to the fragmentation products. The calculated energy of activation for the initial electron transfer was estimated from the crossing of the energy profiles of the neutral molecule and its radical anion (in the form of Morse-like potentials) as a function of the S-S bond length coordinate. The inner intrinsic barrier obtained in this way is in good agreement with that determined by convolution voltammetry, once the solvent effect is taken into account.     

Understanding electron transfer across negatively-charged Aib oligopeptides

The physicochemical effects modulating the conformational behavior and the rate of intramolecular dissociative electron transfer in phthalimide-Aibn-peroxide peptides (n = 0-3) have been studied by an integrated density functional/continuum solvent model. We found that three different orientations of the phthalimide ring are possible, labeled Phihel, PhiC7, and PhipII. In the condensed phase, they are very close in energy when the system is neutral and short. When the peptide chain length increases and the system is negatively charged, Phihel becomes instead the most stable conformer. Our calculations confirm that the 3(10)-helix is the most stable secondary structure for the peptide bridge. However, upon charge injection in the phthalimide end of the phthalimide-Aib3-peroxide, the peptide bridge can adopt an alpha-helix conformation as well. The study of the dependence of the frontier orbitals on the length and on the conformation of the peptide bridge (in agreement with experimental indications) suggests that for n = 3 the process could be influenced by a 3(10) --> alpha-helix conformational transition of the peptide chain.